PROJECT SUMMARY Asthma is a chronic inflammatory lung disease afflicting millions of people showing increased incidence over the past decade. This T cell-mediated disease in allergic asthma is typically thought of as a type 2/Th2 disease, yet precisely how the environmental antigens that trigger asthma initiate Th2 cell development in the lung is unknown. In this application, we describe Blimp-1 as an unexpected regulator of allergen-induced airway inflammation that is critical to promote Th2 cell development in the lung and subsequent airway inflammation. Blimp-1 is a transcriptional repressor that is pleiotropically expressed by effector T cells, and whose role is to regulate effector T cell responses and constrain T cell-mediated autoimmunity. Our recently published work (Science Immunology 2016) has demonstrated that the anti-inflammatory cytokine IL-10 acting through STAT3 is sufficient to induce Blimp-1 in Th2 cells both in vitro and in vivo. Herein, we propose that another STAT3-activating cytokine, IL-6, previously shown to promote allergic experimental asthma downstream of c-kit on dendritic cells, induces Blimp-1 in Th2 cells to initiate Th2 cell development by a hitherto unappreciated mechanism involving effects on Bcl6 and GATA-3, which in turn promotes allergic airway inflammation. We will test our hypothesis in two aims. We will test the prediction that 1) STAT3 is a critical proximal signal that regulates Blimp-1 in Th2 cells during allergic airway disease to suppress Bcl6 and upregulate GATA-3 in T cells, and 2) Blimp-1 is an essential transcriptional regulator that drives pathological Th2 cells during allergic airway inflammation. These studies will elucidate a paradoxical role of Blimp-1 in T cells to either promote or constrain effector T cell responses depending on the context and potentially uncover a novel mechanism linking IL-6 to induction of Th2 cells through expression of Blimp-1. Besides its role in Th2 differentiation, GATA-3 also has an essential role in thymic T cell development, therefore targeting GATA-3 can be expected to have broad effects. The present study is significant because of its potential to establish a novel therapeutic target, Blimp-1, to specifically blunt Th2 cell generation and disease without being broadly immunosuppressive.